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BACKGROUND: Checkpoint-blockade immunotherapy targeting programmed cell death protein 1 (PD-1) has recently shown promising efficacy in hepatocellular carcinoma (HCC). However, the factors affecting and predicting the response to anti-PD-1 immunotherapy in HCC are still unclear. Herein, we report the dynamic variation characteristics and specificities of the gut microbiome during anti-PD-1 immunotherapy in HCC using metagenomic sequencing. RESULTS: Fecal samples from patients responding to immunotherapy showed higher taxa richness and more gene counts than those of non-responders. For dynamic analysis during anti-PD-1 immunotherapy, the dissimilarity of beta diversity became prominent across patients as early as Week 6. In non-responders, Proteobacteria increased from Week 3, and became predominant at Week 12. Twenty responder-enriched species, including Akkermansia muciniphila and Ruminococcaceae spp., were further identified. The related functional genes and metabolic pathway analysis, such as carbohydrate metabolism and methanogenesis, verified the potential bioactivities of responder-enriched species. CONCLUSIONS: Gut microbiome may have a critical impact on the responses of HCC patients treated with anti-PD-1 immunotherapy. The dynamic variation characteristics of the gut microbiome may provide early predictions of the outcomes of immunotherapy in HCC, which is critical for disease-monitoring and treatment decision-making.

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PURPOSE: Motion management is critical for the efficacy of carbon ion therapy for moving targets such as lung tumors. We evaluated the feasibility of using four-dimensional cone beam computed tomography (4D-CBCT) reconstructed by Simultaneous Motion Estimation and Image Reconstruction (SMEIR) for dose calculation and accumulation in carbon ion treatment of lung cancer. METHODS: Motion-compensated 4D-CBCT images were reconstructed with the SMEIR algorithm to capture the most updated anatomy and motion with an updated interphase motion model on the treatment day. Projections of all CBCT phases were simulated from the planning 4D-CT by the ray tracing technique. Treatment planning and dose calculation were performed with a GPU-based Monte Carlo dose calculation software for carbon ion therapy. The treatment plan was optimized on the average computed tomography (CT) to obtain optimal intensity of the carbon ions. From the optimized plan, dose distributions on individual phases of 4D-CT and 4D-CBCT were calculated by the Monte Carlo-based dose engine. Dose accumulation was performed on 4D-CBCT images using deformable vector fields (DVF) generated by SMEIR. The accumulated planning target volume (PTV) dose based on 4D-CBCT was then compared to the accumulated dose calculated on 4D-CT, where the DVFs between different phases were obtained by the demons deformable registration algorithm. RESULTS: Dose value histograms (DVH) as well as absolute deviations of the maximum dose ( Δ D max ), mean dose ( Δ D mean ), and dose coverage metrics ( Δ V 95 % and Δ V 100 % ) for PTV were quantitatively evaluated for the two sets of plans. Good agreement was found between the 4D-CT and 4D-CBCT-based PTV-DVH curves. The average values of Δ D max , Δ D mean , Δ V 95 % , and Δ V 100 % calculated between the 4D-CT and SMEIR-4D-CBCT-based plans were 1.91 % , 3.55 % , 2.12%, and 1.15 % , respectively, for the PTVs of ten patient case studies. CONCLUSIONS: Based on these results, SMEIR-reconstructed 4D-CBCTs can potentially be used for motion estimation, dose evaluation, and adaptive treatment planning in lung cancer carbon ion therapy.

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To investigate the parameters associated with post-treatment recurrence of bacterial vaginosis (BV), clinical factors and vaginal microbiota were examined and analyzed for BV patients who received standard metronidazole therapy. The variables associated with BV recurrence included clinical factors of past BV history, use of intravaginal device, and D7 Nugent score as well as many microbial genera, with Lactobacillus, Enterococcus, Ureaplasma, and Aerococcus being the top contributors. Co-occurrence network analysis showed that whereas overwhelming majority of interbacterial interactions were positive, negative interactions were present and connected mostly to Lactobacillus, Enterococcus, and to a less extent Ureaplasma, suggesting the importance of interbacterial antagonism for treatment outcome. The patients who were cured and recurrent also exhibited clear differences in the species composition of Lactobacillus: although L. iners remained the dominant species at all time points, L. crispatus, L. gasseri, and L. jensenii displayed apparent differences in relative abundance between the cure and recurrent groups. Based on these results, we developed a 5-component panel comprising Enterococcus, L. crispatus, Ureaplasma, Aerococcus, and L. jensenii for predicting recurrence using D7 data and showed that it generated the specificity, sensitivity, and AUC values of 0.80, 0.66, and 0.73 for the discovery cohort and 0.80, 0.67, and 0.69 for the validation cohort. Our findings highlighted key microbial components for BV recurrence and suggested that they could be used to monitor the treatment outcome.

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The abuse of fentanyl and its analogues, which are potent, short-acting, synthetic narcotic analgesics, has become a major issue. Many cases containing fentanyl-analogue and novel synthetic opioids have also been reported. Hence, we report the determination of fentanyl, fentanyl-analogue and novel synthetic opioids in whole blood by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The method is characterized by the use of a simple, fast and inexpensive liquid-liquid extraction (LLE) for sample preparation, a rapid run time (8â¯min) and a low required volume of whole blood (100â¯µl). The limits of detection (LODs) ranged from 0.005 to 0.03â¯ng/ml, and the lower limits of quantitation (LLOQs) ranged from 0.05 to 0.2â¯ng/ml. The method was shown to be liner over a concentration range of 0.2-40â¯ng/ml for fentanyl, norfentanyl and norcarfentanil and 0.05-40â¯ng/ml for all other target analytes. Recoveries were within the range of 72.09%-103.22%, and the matrix effects were in the 67.95%-113.32% range. Moreover, the method was applied to the detection and quantification of fentanyl and its analogues in whole blood from real forensic cases. This methodology has great potential for use in the determination of fentanyl and its analogues in forensic cases.

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OBJECTIVES: Microbiota dysbiosis in inflammatory bowel disease (IBD) has been widely reported. The gut microbiota connect diet to the metabolism by producing small molecules via diverse metabolic pathways. In this study we aimed to investigate the dietary preferences of IBD patients, and to explore the interactions among gut microbiota composition, dietary components, and metabolites in relation to IBD. METHODS: Dietary preferences of IBD patients (including those with ulcerative colitis [UC] and Crohn's disease [CD]) and health controls were investigated, and their gut microbiota were analyzed using 16S rRNA gene sequencing and metagenomic analyses of fecal and biopsy samples. The metabolite profiles of the samples were then analyzed using gas and liquid chromatography-mass spectrometry analyses. RESULTS: The daily intake of folic acid, niacin, vitamins C and D, calcium, and selenium differed significantly between patients with IBD and healthy controls. A decrease in long-chain (such as arachidic, and oleic acid) and medium-chain fatty acids (sebacic acid and isocaproic acid) as well as bile acid was observed in patients with IBD. Compared with healthy controls, 22 microbial species (including Sulfolobus acidocaldarius, and Clostridium clostridioforme CAG132) in the UC group and 37 microbial species (such as Bacteroides fragilis and Fusobacterium nucleatum) in the CD group were found to be correlated to diet and metabolites. Bacteroides fragilis was enriched in patients with IBD and associated with multi-nutrients, and 21 metabolites including 25-hydroxyvitamin D3 and taurolithocholic acid. CONCLUSIONS: This study provides an interaction network to identify key micronutrients, microbiota components and metabolites that contribute to IBD.

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Medulloblastoma is the most common malignant brain cancer in children. Since previous studies have mainly focused on alterations in the coding genome, our understanding of the contribution of long noncoding RNAs (lncRNAs) to medulloblastoma biology is just emerging. Using patient-derived data, we show that the promoter of lncRNA TP73-AS1 is hypomethylated and that the transcript is highly expressed in the SHH subgroup. Furthermore, high expression of TP73-AS1 is correlated with poor outcome in patients with TP53 wild-type SHH tumors. Silencing TP73-AS1 in medulloblastoma tumor cells induced apoptosis, while proliferation and migration were inhibited in culture. In vivo, silencing TP73-AS1 in medulloblastoma tumor cells resulted in reduced tumor growth, reduced proliferation of tumor cells, increased apoptosis and led to prolonged survival of tumor-bearing mice. Together, our study suggests that the lncRNA TP73-AS1 is a prognostic marker and therapeutic target in medulloblastoma tumors and serves as a proof of concept that lncRNAs are important factors in the disease.

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In vertebrates, tumor necrosis factors (TNFs) are well-known cytokines involved in a diversity of physiological and pathological events. In the present work we identified a novel TNF-like gene (MnTNF) from Macrobrachium nipponense, which codes for a protein sharing detectable sequence identify (26-27%) to the mammalian TNFSF members, TWEAK and EDA. Tissue distribution analysis indicated that MnTNF was predominantly expressed in nervous tissue, and at relatively high level in haemocytes, gill, intestine and muscle, whereas was almost undetectable in hepatopancreas. In gill, MnTNF was significantly up-regulated at both mRNA as well protein levels upon Aeromonas veronii challenge. RNA interference (RNAi) mediated MnTNF silencing led to a significant overexpression of the antimicrobial peptide (AMP) gene crustin, but a non-significant overexpression of another AMP gene anti-lipopolysaccharide factor (ALF), and inhibited the activation of phenoloxidase (PO) significantly following bacterial challenge. Meanwhile, the expression of NF-κB-like factor gene relish was increased while that of dorsal and STAT was uninfluenced in MnTNF-depleted prawn. We suppose that MnTNF be involved in regulating the expression of AMP genes and the capacity of PO by coordinating with the Imd pathway.

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Inverse treatment planning in radiation therapy is formulated as solving optimization problems. The objective function and constraints consist of multiple terms designed for different clinical and practical considerations. Weighting factors of these terms are needed to define the optimization problem. While a treatment planning optimization engine can solve the optimization problem with given weights, adjusting the weights to yield a high-quality plan is typically performed by a human planner. Yet the weight-tuning task is labor intensive, time consuming, and it critically affects the final plan quality. An automatic weight-tuning approach is strongly desired. The procedure of weight adjustment to improve the plan quality is essentially a decision-making problem. Motivated by the tremendous success in deep learning for decision making with human-level intelligence, we propose a novel framework to adjust the weights in a human-like manner. This study used inverse treatment planning in high-dose-rate brachytherapy (HDRBT) for cervical cancer as an example. We developed a weight-tuning policy network (WTPN) that observes dose volume histograms of a plan and outputs an action to adjust organ weighting factors, similar to the behaviors of a human planner. We trained the WTPN via end-to-end deep reinforcement learning. Experience replay was performed with the epsilon greedy algorithm. After training was completed, we applied the trained WTPN to guide treatment planning of five testing patient cases. It was found that the trained WTPN successfully learnt the treatment planning goals and was able to guide the weight tuning process. On average, the quality score of plans generated under the WTPN's guidance was improved by ~8.5% compared to the initial plan with arbitrarily set weights, and by 10.7% compared to the plans generated by human planners. To our knowledge, this was the first time that a tool was developed to adjust organ weights for the treatment planning optimization problem in a human-like fashion based on intelligence learnt from a training process, which was different from existing strategies based on pre-defined rules. The study demonstrated potential feasibility to develop intelligent treatment planning approaches via deep reinforcement learning.

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This study was designed to evaluate the potential application of the stems and leaves of Astragalus membranaceus (AMSL) in the poultry industry. Quails were divided into four groups and fed daily with an AMSL-free diet (control) or with 1%, 3%, or 5% (w/w) AMSL-incorporated diets for 35 days. The results showed that supplementing AMSL in the diet, especially at a concentration of 3%, increased daily gain and feed intake during the entire experiment (p

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Intestinal microbiota plays a crucial role in immune development and disease progression in mammals from birth onwards. The gastrointestinal tract of newborn mammals is rapidly colonized by microbes with tremendous biomass and diversity. Understanding how this complex of segmental communities evolves in different gastrointestinal sites over time has great biological significance and medical implications. However, most previous reports examining intestinal microbiota have focused on fecal samples, a strategy that overlooks the spatial microbial dynamics in different intestinal segments. Using intestinal digesta from six intestinal segments (duodenum, jejunum, ileum, cecum, colon and rectum) of newborn piglets, we herein conducted a large-scale 16S rRNA gene sequencing-based study to characterize the segmental dynamics of porcine gut microbiota at eight postnatal intervals (days 1, 7, 14, 21, 28, 35, 120 and 180). A total of 4,465 OTUs were obtained and showed that the six intestinal segments could be divided into three parts; in the duodenum-jejunum section, the most abundant genera included Lactobacillus and Bacteroides; in the ileum, Fusobacterium and Escherichia; and in the cecum-rectum section, Prevotella. Although the microbial communities of the piglets were similar among the six intestinal segments on postnatal day 1, they evolved and quickly differentiated at later intervals. An examination of time-dependent alterations in the dominant microbes revealed that the microbiome in the large intestine was very different from and much more stable than that in the small intestine. The gut microbiota in newborn piglets exhibited apparent temporal and spatial variations in different intestinal segments. The database of gut microbes in piglets could be a referable resource for future studies on mammalian gut microbiome development in early host growth phases.

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Epimedii Folium (EF) combined with Psoraleae Fructus (PF) is a common modern preparation, but liver injury caused by Chinese patent medicine preparations containing EF and PF has been frequently reported in recent years. Zhuangguguanjiewan pills (ZGW), which contain EF and PF, could induce immune idiosyncratic liver injury according to clinical case reports and a nonhepatotoxic dose of lipopolysaccharide (LPS) model. This present study evaluated the liver injury induced by EF or PF alone or in combination and investigated the related mechanism by using the LPS model. Liver function indexes and pathological results showed that either EF or PF alone or in combination led to liver injury in normal rats; however, EF or PF alone could lead to liver injury in LPS-treated rats. Moreover, EF combined with PF could induce a greater degree of injury than that caused by EF or PF alone in LPS-treated rats. Furthermore, EF or PF alone or in combination enhanced the LPS-stimulated inflammatory cytokine production, implying that IL-1ß, which is processed and released by activating the NLRP3 inflammasome, is a specific indicator of EF-induced immune idiosyncratic hepatotoxicity. Thus, EF may induce liver injury through enhancing the LPS-mediated proinflammatory cytokine production and activating the NLRP3 inflammasome. In addition, the metabolomics analysis results showed that PF affected more metabolites in glycerophospholipid and sphingolipid metabolic pathways compared with EF in LPS model, suggesting that PF increased the responsiveness of the liver to LPS or other inflammatory mediators via modulation of multiple metabolic pathways. Therefore, EF and PF combination indicates traditional Chinese medicine incompatibility, considering that it induces idiosyncratic hepatotoxicity under immunological stress conditions.

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ETHNOPHARMACOLOGICAL RELEVANCE: Whitmania pigra Whitman (Whitmania pigra, WP), firstly recorded in the Shennong's Herbal Classic and officially listed in the Chinese Pharmacopoeia, is a well-used cardiovascular protective traditional Chinese medicine derived from leeches. Traditional Chinese physicians prefer to prescribe the dried whole body of leech processed under high temperatures. It has been reported that dried WP remains clinically effective. However, the therapeutic mechanism has yet not be clearly elucidated. AIM OF THE STUDY: This study was designed to investigate the protective activity of the extract of WP in a high-molecular-weight dextran-induced blood hyperviscosity rat model, and to explore the role of WP in improving blood hyperviscosity related metabolic disorders and to clarify the possible mechanism of metabolic regulation. MATERIALS AND METHODS: The hemorheological parameters were measured with an automated blood rheology analyzer. Hematoxylin-eosin staining was used to observe the pathological changes in aortic tissues samples. Further, a liquid chromatography-mass-spectrometry (LC-MS)-based untargeted metabolomics approach was applied to characterize the metabolic alterations. RESULTS: WP has evident attenuating effects on blood hyperviscosity and related metabolic disorders, and the influences are distinct from those of aspirin. The results showed that WP had good effects in reducing blood viscosity and ameliorating histopathological changes in the thoracic aorta in a high molecular weight dextran-induced blood hyperviscosity rat model. The middle dose (2.5â¯g raw material/kg body weight) of WP exhibited effects equivalent to aspirin (100â¯mg/kg) on hemorheological and histopathological parameters (Pâ¯>â¯0.05). However, when using metabolomics profiling, we found that WP could significantly improve blood hyperviscosity-related metabolic disorders and restore metabolites to normal levels; while aspirin showed little effect. With principal component analysis and orthogonal partial least-squares discriminant analysis, WP regulated many more endogenous metabolites than aspirin. With pathway enrichment analysis, the differential endogenous metabolites were involved in cysteine and methionine metabolism, TCA cycle, arachidonic acid metabolism, etc., highlighting the metabolic reprogramming potential of WP against blood hyperviscosity-induced metabolic disorders. CONCLUSIONS: The study suggest that WP has a more potent effect, but a different mechanism, than aspirin in improving either blood hyperviscosity or related metabolic disorders associated with cardio- and cerebrovascular diseases.

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In order to understand the genetic diversity and structure within and between the genera of Saccharum and Erianthus, 79 accessions from five species (S. officinarum, S. spontaneum, S. robustum, S. barberi, S. sinense), six accessions of E. arundinaceus, and 30 Saccharum spp. hybrids were analyzed using 21 pairs of fluorescence-labeled highly poloymorphic SSR primers and a capillary electrophoresis (CE) detection system. A total of 167 polymorphic SSR alleles were identified by CE with a mean value of polymorphic information content (PIC) of 0.92. Genetic diversity parameters among these 115 accessions revealed that Saccharum spp. hybrids were more diverse than those of Saccharum and Erianthus species. Based on the SSR data, the 115 accessions were classified into seven main phylogenetic groups, which corresponded to the Saccharum and Erianthus genera through phylogenetic analysis and principle component analysis (PCA). We propose that seven core SSR primer pairs, namely, SMC31CUQ, SMC336BS, SMC597CS, SMC703BS, SMC24DUQ, mSSCIR3, and mSSCIR43, may have a wide appicability in genotype identification of Saccharum species and Saccharum spp. hybrids. Thus, the information from this study contibites to manage sugarcane genetic resources.

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Activity participation is essential to the wellbeing of aging adults. Divergent levels of activity participation within aging populations have been explained from diverse perspectives, but the interaction effects of key determinants, such as personality and health, are often ignored. This study examines the effects of extravert personality on aging adults' activity levels by addressing its interaction with perceived physical health and mental health. A sample of 304 adults aged 50 and older was selected using systematic sampling from participants of an institute for promoting active aging at a university in Hong Kong in 2017. Data on socio-demographic characteristics, perceived physical and mental health, extraversion personality traits, and level of activity participation were collected using a telephone survey. Most participants (46.7%) reported moderate activity levels and over a quarter (26.6%) reported high or low activity levels. Multi-nominal logistic regression analyses show that extraversion was associated with an increased likelihood of reporting moderate (OR = 1.85, p = .036) but not high (p > .05) activity levels when adjusted for perceived physical and mental health and socio-demographics, with low activity levels being the constant comparison. Meanwhile, extraversion predicted both moderate (OR = 3.84, p = .014) and high (OR = 5.06, p = .032) activity levels for participants with poor or average perceived mental health. However, the interaction effects of extraversion with perceived physical health or mental health were not significant in predicting either moderate or high activity levels (p > .05). The implications for enhancing activity participation among aging adults are discussed in view of both personality and perceived health status.

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Acute kidney injury (AKI) is a public health concern with high morbidity and mortality rates in hospitalized patients and because survivors have increased risk of progression to chronic kidney disease. Mitochondrial damage is the critical driver of AKI-associated dysfunction and loss of tubular epithelial cells; however, the pathways that mediate these events are poorly defined. Here, in murine ischemia/reperfusion-induced (I/R-induced) AKI, we determined that mitochondrial damage is associated with the level of renal uncoupling protein 2 (UCP2). In hypoxia-damaged proximal tubular cells (PTCs), a disruption of mitochondrial dynamics demonstrated by mitochondrial fragmentation and disturbance between fusion and fission was clearly indicated. Ucp2-deficient mice (knockout mice) with I/R injury experienced more severe AKI and mitochondrial fragmentation than wild-type (WT) mice. Moreover, genetic or pharmacologic treatment increased UCP2 expression, improved renal function, reduced tubular injury and limited mitochondrial fission. In cultured proximal tubular epithelial cells, hypoxia-induced mitochondrial fission was exacerbated in cells with UCP2 deletion, while an increase of UCP2 ameliorated the hypoxia-induced disturbance of the balance between mitochondrial fusion and fission. Furthermore, results following modulation of UCP2 suggested it has a role in preserving mitochondrial integrity by preventing loss of membrane potential and reducing subsequent mitophagy. Taken together, our results indicate that UCP2 is protective against AKI and suggest that enhancing UCP2 to improve mitochondrial dynamics has potential as a strategy for improving outcomes of renal injury. This article is protected by copyright. All rights reserved.

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OBJECTIVES: This study examined the associations between perceived crime-specific victimization risk, avoidance behavior, and their relationships with health of older adults. METHOD: A representative sample of 453 Chinese aged 60 and older from Kunming provided information on their socio-demographic characteristics, perceived crime victimization risk, avoidance behavior, physical and mental health. RESULTS: Avoidance behavior was common among participants, with 61.4% avoiding unsafe areas and 42.2% avoiding social activities. Path analyses showed that perceived risk of vandalism was associated with avoiding participating in social activities, while perceived risk of attack was related to avoiding unsafe areas during the day. Meanwhile, avoiding social activities and perceived risk of vandalism were significant predictors of poor mental health, and avoiding unsafe areas was a salient predictor of poor physical health. Perceived risk of attack had an indirect effect on physical health through avoiding unsafe areas during the day. CONCLUSION: Study findings highlight the importance of addressing perceived victimization risk in encouraging social participation and mobility among older adults.

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Previous studies have identified recurrent oncogenic mutations in colorectal cancer (CRC), but there is limited CRC genomic data from the Chinese Han population. Whole­genome sequencing was performed on 10 primary CRC tumors and matched adjacent normal tissues from patients from the Han population in Shanghai, at an average of 27.8x and 27.9x coverage, respectively. In the 10 tumor samples, 32 significant somatic mutated genes were identified, 13 of which were also reported as CRC mutations in The Cancer Genome Atlas Network. All the mutated genes were enriched in functions associated with channel activity, which has rarely been reported in previous studies investigating CRC. Furthermore, 21 chromosomal rearrangements were detected and 4 rearrangements encoded predicted in­frame fusion proteins, including a fusion of phosphorylase kinase regulatory subunit b and NOTCH2 demonstrated in 2 out of 10 tumors. Chromosome 8 was amplified in 1 tumor and chromosome 20 was amplified in 2 out of 10 CRC patients. The present study produced a genomic mutation profile of CRC, which provides a valuable resource for further insight into the mutations that characterize CRC in patients from the Han population in Shanghai, eastern China.

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The current consensus recognizes four main medulloblastoma subgroups (wingless, Sonic hedgehog, group 3 and group 4). While medulloblastoma subgroups have been characterized extensively at the (epi-)genomic and transcriptomic levels, the proteome and phosphoproteome landscape remain to be comprehensively elucidated. Using quantitative (phospho)-proteomics in primary human medulloblastomas, we unravel distinct posttranscriptional regulation leading to highly divergent oncogenic signaling and kinase activity profiles in groups 3 and 4 medulloblastomas. Specifically, proteomic and phosphoproteomic analyses identify aberrant ERBB4-SRC signaling in group 4. Hence, enforced expression of an activated SRC combined with p53 inactivation induces murine tumors that resemble group 4 medulloblastoma. Therefore, our integrative proteogenomics approach unveils an oncogenic pathway and potential therapeutic vulnerability in the most common medulloblastoma subgroup.

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